2-(2-hydroxy-3-aminopropyl-1-yloxy)-1,6-dilfuoro-and-1,6-methano-{8 10{9 annulenes and the salts thereof

ABSTRACT

Disclosed herein are certain 2-(2-hydroxy-3-amino or substituted aminoprop-1-yloxy)-1,6-methano- or -1,6difluoromethano(10)annulene compounds and various ring substituted derivatives thereof. Methods for the preparation of these compounds and novel intermediates useful in these methods are also disclosed. The product compounds, described above, are useful Beta -adrenergic blocking agents. 2-(2-Hydroxy-3isopropyl-aminoprop-1-yloxy)-1,6-methano(10)annulene and 2-(2hydroxy-3-isopropylaminoprop-1-yloxy)-1,6difluoromethano(10)annulene are illustrated as representative of the compound class.

United States Patent 11 1 Nelson et al.

l lSept. 11,1973

[75] Inventors: Peter H. Nelson; Karl G. Untch, both of Los Altos; John H. Fried, Palo Alto, all of Calif.

[73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Jan. 21, 1971 [21] Appl. No.: 108,611

[52] US. Cl. 260/570.7, 260/247.2 A, 260/247.2 B, 260/247.7 R, 260/268 R, 260/286 R,

260/294, 260/294.3, 260/294.7, 260/307 R, 260/326.5 L, 260/326.5 R, 260/348 A,

260/348 R, 260/404, 260/471 C, 260/479 R, 260/479 C, 260/501.l R, 260/556 A, 260/562 R, 260/562 A, 260/612 R, 260/618 R,

260/649 R, 260/649 F, 260/668 R, 260/248, 260/649 R, 260/649 F, 260/668 R, 424/248,

[51] Int. Cl C07c 93/06 [58] Field of Search 260/570.7, 501.18

[56] References Cited UNITED STATES PATENTS 3,415,873 l2/l968 Stevens 260/570.7 X 3,432,545 3/1969 Howe 260/570.7 X

Primary Examiner-Robert V. Hines Attorney-Evelyn K. Merker, Gerard A. Blaufarb and Walter H. Dreger [5 7] ABSTRACT Disclosed herein are certain 2-(2-hydroxy-3-amino or substituted aminoprop-l-yloxy)-l,6-methanoor -1,6- difluoromethano[101annulene compounds and various ring substituted derivatives thereof. Methods for the preparation of these compounds and novel intermediates useful in these methods are also disclosed. The product compounds, described above, are useful fi-adrenergic blocking agents. 2-(2-Hydroxy-3-isopropylaminopropl -yloxy )l ,6-methano[ l0]annulene and 2-( 2-hydroxy-3-isopr0pylaminopropl -yloxy )-l ,6- difluoromethano[101annulene are illustrated as representative of the compound class.

20 Claims, No Drawings 1 2-(2-HYDROXY-3-AMIN()PR()PYL-l-YLOXY)-l ,6- DlLFUORO-AND-l,6-METHANO-[ lOIANNULENES AND THE SALTS THEREOF The present invention relates to novel hydroxyamino-propyloxy annulene compounds, their use, and processes and novel intermediates useful for their preparation.

The principal hydroxyaminopropyloxy annulene compounds of the present invention can be represented by the following Formula A:

and those hydroxyaminopropyloxy annulene compounds of the present invention containing additional ring substituents can be represented by the following Formulas B, C, D, E, F, G, and H:

R V o H N H N\ l n l R1 V B o o H N 0 H N i R I Rl R R1 M 0% 5 R l OH \R1 I \R 3 i X2 Y O I o\ F (1 Bl N N I OH Rl @Q.

OH M In the above A to H and succeeding formulas: X is hydrogen or :fluoro;

each R is hydrogen, alkyl of one to eight carbon atoms, inclusive, cycloalkyl of three to six carbon atoms, inclusive, benzyl, phenylbut-3-yl, or, when both are taken together with the nitrogen atom, morpholino, pyrrolidino, piperidino, or piperizino, or 4-lower alkyl piperizino;

R' is R or, when R" is hydrogen, acetyl;

R is allyl or alkyl of one to three carbon atoms;

R is allyl or alkyl of one to three carbon atoms;

R is chloro, alkyl or alkenyl, each of up to six carbon atoms, hydroxy, allyloxy, alkyloxy of one to three carbon atoms, carboxylic acyloxy of up to six carbon atoms, carbamyloxy, N-(lower)alkylcarbamyloxy, N,N-di(]ower)alkylcarbamyloxy, nitro, alkoxy (up to six carbon atoms)-carbonylamino, carbamyl-amino, N-methyl carbamylamino, N,N- dimethylcarbamylamino, amino, or monosubstituted amino wherein the substituent is acyl, mesyl, formyl, alkyl of one to six carbon atoms, inclusive, alkenyl of two or three carbon atoms; and

each of R and R is chloro, hydroxy, allyloxy, al-

kyloxy of one to three carbon atoms, or carboxylic acyloxy of up to six carbon atoms.

Also included within the scope of the depicted and herein described compounds of the present invention are the pharmaceutically acceptable non-toxic salts thereof.

Also included within the scope of the present invention are the oxazolidine derivative compounds of the compounds of the above fonnulas wherein the C-2 side chain has the following formula:

wherein R is hydrogen, alkyl of one to eight carbon atoms, inclusive, cycloalkyl of three to six carbon atoms, inclusive, benzyl, or phenyl-but-3-yl and each of R and R is hydrogen, alkyl of up to six carbon atoms or, when taken together with the carbon atom, cycloalkyl of three to six carbon atoms,

The compounds of the present invention are B-adrenergic blocking agents and are thus valuable in the treatment of symptoms for which such agents are indicated such as hypertension, angina pectoris, coronary insufficiency, and so forth. In this use, the compounds of the present invention can .be administered and employed in the same manner as known B-adrenergic blocking agents such as propranolol hydrochloride.

The compounds of the present invention are prepared conveniently through a series of reactions. The compounds of the present invention of Formula A can be prepared as depicted in the following reaction Sequence A:

Sequence A O OJLCH; Br

(iCH; Br

O I i: z

With

reference to Sequence A, l,6-methano- [l]annulene l is converted to the corresponding 2,5- diacetoxy-2,5-dihydro compound 3 by treatment with lead tetraacetate. Thereafter, the 2,5-diacetoxy compound 3 is reacted with a stoichiometric excess of 2,3- oxido-l-propanol (glycidol), for example, at a temperature of from about 30 to about 150C, to prepare the reaction mixture represented by Formulas 5 and 6, namely the 2-(2,3-oxidoprop-l -yloxy)-5-acetoxy compound 5 and the 2,5-bis(2,3-oxid0propl-yloxy) compound 6 each wherein X is hydrogen. The compound of Formula 5 is thereafter converted to the compound of Formula 7 by elimination of the S-acetoxy group, for example, at a temperature of from about 25C. to about 200C., preferably in an organic solvent. Similarly, the compound of Formula 6 can be converted to the corresponding compound of Formula 7 by treatment with, for example, potassium t-butoxide in glyme. Alternatively, the diacetate 3 can be converted to the compound of Formula 7 by treatment with glycidol in the presence of an acid, such as p-toluenesulfonic acid. The resultant l,6-methano-(2,3-oxidoprop-l-yloxy)- [l0]annulene compound 7 is treated with ammonia or a primary or secondary amine (dictated by the definitions of R in the above formulas) to prepare the products of the present invention represented by Formula A.

In the l,6-difluoromethano-[l0]annulene series, the l,6-difluoromethano-[ l0]annulene 2 is converted to the corresponding dibromo compound 4 by treatment with bromine in a halogenated solvent, such as carbon tetrachloride. Thereafter, the dibromo compound 4 is treated with a stoichiometric excess of glycidol to form the 2,5-bis(2,3-oxidoprop-l-yloxy) compound 6 together with 2-( 2,3-oxido-propl -yloxy)-l ,6- difluoromethano-[l0]annulene 7 each wherein X is fluoro. These compounds can be isolated by chromatography. Compound 6 wherein X is fluoro is then converted to compound 7 if desired, and thence to A as described above.

The compounds represented by Formulas l and 2 are known compounds or they can be prepared in accordance with procedures known per se. For example, by treating naphthalene with an alkali metal and alcohol in a solvent such as a lower alkyl amine or diamine or in liquid ammonia there is prepared the corresponding l,4,5,8-tetrahydronaphthalene compound. This compound is converted to the corresponding 9,10-bridgedl ,4,5,8,9,1 O-hexahydronaphthalene compound wherein the bridged moiety is methano or difluoromethano by treatment of the triene with carbene or difluorocarbene. The difluorocarbene reactant is generated from a haloform and an alkali metal tertiary alkoxide; or from alkali or alkaline earth metal salt of a trihaloacetic acid, or from a phenyltrihalomethyl mercury. The carbene or methylene group is generated from zinczcopper couple methylene iodide reagent which is prepared from zinc dust, a copper salt such as cuprous chloride and methylene iodide.

Following the preparation of the bridged compound, it is treated with a benzoquinone such as 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone in the presence of inert liquid organic reaction medium at a temperature ranging from about 0C. up to the boiling point of the reaction mixture and under reflux to prepare the corresponding l,6-methano or 1,6-difluoromethano- [l0]annulene compound 1 and 2.

The compounds represented by Formulas 5 and 6 are obtained as a mixture from compound 3. This mixture can be separated via conventional techniques such as chromatography to separate and isolate the respective compounds which are useful as described above.

The compounds of the present invention represented above by Formulas B and C can be prepared as depicted in the following reaction Sequence B.

equence B gr M g! R H H F wherein R is as defined by R and R above.

With reference to Sequence B above, the B- or 2- substituted naphthalene compound 8 is reduced such as via the Birch conditions with an alkali metal and an alcohol in a solvent such as a lower alkyl amine or diamine such as methylamine, diethylamine, and the like or in liquid ammonia. Thereafter, the product compound 9 is reacted as set forth above so as to add the CX group across the 9,10-double bond to prepare compounds 10 which can be treated with 2,3-dichloro- 5,6-dicyano-1,4-benzoquinone as set forth above, to prepare the 3-substituted-[ l]annulene compounds represented by Formula ll. Thereafter, the compounds of Formula 11 are treated with lead tetraacetate followed by heating at a temperature of from 25 to 150C. and under acidic conditions so as to prepare the mixture of isomers represented by compounds 12 and 13. These isomers can be separated from the reaction mixture via conventional techniques such as chromatography.

The compounds of Formulas l2 and 13 can be base hydrolyzed so as to cleave the acetoxy group and thereafter treated with epibromohydrin and a base so as to add the glycidol side chain at the 2 position of the molecule, followed by amine treatment to respectively prepare the compounds of Formulas B and C.

Alternatively, the compound of Formula 11 wherein X is fluoro can be acylated at the 2 and positions by treatment thereof with acetic anhydride and stannic chloride followed by a Baeyer-Villiger oxidation so as to prepare the isomeric products represented by Formulas l2 and 13, wherein X is fluoro. These isomers can be separated via conventional techniques such as chromatography and each treated in accordance with the sequence set forth above, namely base hydrolysis, addition of the side group, and amine treatment to respectively prepare the compounds of Formulas B and C above.

A particularly useful method for preparing the compounds of Formula B above wherein R is allyl is illustrated below by Sequence C:

b'equcnca C 06cm /\2 c cn3 Br 0 a l 7 l 0 T BX; m

o OH V 17 is R O/\/\N/ l on R1 CE,

I ox,

With reference to Sequence C, the diacetate compound 3 is converted to the diallyloxy compound 14 by treatment with a stoichiometric excess of allyl alcohol. Alternatively, treatment of the diacetate with allyl alcohol in the presence of p-toluenesulfonic acid affords the monoallyloxy compound 15. The bisallyloxy compound l4 can be converted to the mono-allyloxy 15 by separate treatment with p-toluenesulfonic acid in an organic solvent. The dibromo compound 4 in the difluoromethano series is similarly converted to compounds 14 and 15, wherein X is fluoro.

Compound 15 is then subjected to a Claisen rearrangement catalysed either by heat, ultraviolet irradiation or mineral acids to prepare the 2-hydroxy-3- allyloxy compound 16. This compound is reacted with epibromohydrin to produce compound 17 and the latter converted to compound B, as described above.

Certain of the compounds of the present invention represented above by Formula D, G, and H are pre- Sequence D (can't) pared as more particularly described and depicted as follows by Sequence D and the text that follows.

Sequence D R is allyloxy or alkyloxy of one to three carbon atoms;

R" is hydroxy or carboxylic acyloxy of up to six carbon atoms;

R' is alkyl or alkenyl; and

R is carbamyloxy, N-(lower)-alkylcarbamyloxy or N,N-di(lower)alkylcarbamyloxy.

With reference to Sequence D, compound 5, which is prepared as described above in Sequence A, is treated sequentially first with an alkali metal hydroxide, for example, in aqueous methanol and second with manganese dioxide to prepare the tautomeric equilibrium mixture as represented by formulas l8 and 18'. The tautomer represented by formula 18 may be present in predominant amounts and can be separated from the tautomer of formula 18', such as by base extraction of 18'. In the preferred embodiments, the mixture represented by formulas 18 and 18' is not resolved but is used as such in the subsequent reactions. For the sake of convenience and simplicity, reference to the oxo-2,5-dihydro tautomer (18) by name and formula is intended as representative to each and both forms. The dibromo compound, in the difluoromethano series 4 is likewise converted to the tautomeric mixture 18,18 by conversion to the corresponding diacetate with acetic acid and sodium acetate and base hydrolysis thereof to the corresponding diol followed by treatment of the latter with epibromohydrin and sodium hydride, followed by oxidation, for example, with manganese dioxide.

Thereafter, compound 18,18 is converted to the corresponding 5-substituted compounds of Formula 19, wherein the substituent is an oxygenated function, by reaction with potassium t-butoxide, e.g. in glyme, and the appropriate bromide, i.e. allyl bromide or an alkyl bromide. The compounds of Formula 19 are then treated with amine as set forth above to prepare the compounds of Formula D which by reference to the compounds of Formula D are those wherein R is as de fined by R.

Alternatively, the compound of Formula 18,18 is treated with potassium t-butoxide and acetyl chloride to prepare the compounds of Formula 20 wherein R- is acetoxy. The corresponding hydroxy compound (20,R hydroxy) is prepared by subsequent base hydrolysis. The hydroxy compound can be conventionally esterifie'd to prepare the other ester compounds of the present invention in the C--5 substituted series. Thereafter, treatment with amine, as above described affords the products D corresponding to products D wherein R is as defined by R. The S-acetate of formula D can be treated with base to afford the S-keto (hydroxy tautomer) D. This compound D can be converted to the C5 alkyl or alkenyl products D by standard Grignard conditions after prior reversible protection of the hydroxy, amino side chain with oxazolidine formation and acid or base hydrolysis.

The compound 18,18 can be converted to the 5- chloro compound 21 by treatment with catecholphosphotrichloride in chloroform followed by amine treatment as described above, or to the bis glycidol ether compound 22 by treatment with epibromohydrin and potassium t-butoxide in glyme. The latter 22 is ring opened with one equivalent of amine, as described above to form the compounds of the present invention of formula G. The latter can be ring opened with a second equivalent of the same or a different amine, as desired, to form the compounds of the present invention of formula H. Alternatively, the compounds of formula G wherein one of R is H can be acetylated by treatment with acetic anhydride in pyridine to give 24 and the latter ring opened to provide the compounds of the present invention of formula H.

The compound 18,18. can be treated with potassium t-butoxide and ethylchloroformate to the 5- ethoxycarbonyloxy compound 23. This, when treated with one equivalent of amine as described above, affords he corresponding ring opened compounds 25. The latter are treated, if desired with ammonia or a monoalkyl or a dialkyl amine to afford the compounds of formula D.

The compounds of Formula D wherein R is amino or monosubstituted amino are prepared as follows (Sequence D):

Sequence D NH; R" 27 28 R1 M O l N OH wherein R- is nitro, amino or monosubstituted amino, the substituents beingas defined above in the definition of R, and R" is R, exclusive of amino.

With reference to Sequence D, compound 7, prepared as described above, is treated with cupric nitrate trihydrate in acetic anhydride to prepare the nitro com pound 26. This compound is converted to the amine 27 by hydrogenation over palladium on charcoal catalyst. The latter amine is treated with amine as described above to prepare the products 6 wherein R- is amino.

Alternatively, the amine 27 can be mono substituted compounds 28 by treatment with a carboxylic acid anhydride to the mono acyl compound or with methanesulfonyl chloride to the mono mesyl compound or with ethyl formate to the .mono-formyl compound or with benzyl chloride to the monobenzyl compound or with an alkyl or alkenyl chloride to the monoalkyl or monoalkenyl compound of formula 28. In addition, the amine compounds can be treated with an alkyl chloroformate to prepare the alkoxycarbonylamino compounds and the latter with an amine to form the carbamyl and substituted carbanyl-amino compounds of formula 28. Compounds 28 are converted to the products D as described above.

The compounds of the present invention of Formulas E and F above are prepared in accordance with the reactions depicted in Sequence E and described in the text which follows Sequence E, as follows:

o Y I l -R1 N-R i Hz on: i B H3 on:

/R1 /R1 m M H H OH H I Y I l l Y wherein Y is bromo or chloro; and each of R"- and R"' is hydroxy, allyloxy, alkyloxy or carboxylic acyloxy.

With reference to the above reaction Sequence E, compound 3 or 4', which is prepared as described above, is chlorinated or brominated to prepare the corresponding dihalo compound 25. This compound is then heated or treated with diazabicyclononene to prepare a mixture of compounds, namely, the 2-acetoxy-7- halo and 2-acetoxy-l0-halo compounds depicted by 26 and 27. These compounds can be separated via conventional techniques and thereafter separately, but identically treated. For example, a compound of Formulas 26and 27 can be base hydrolyzed, treated with epibromohydrin, reacted with amine, and then treated with acetone to prepare the respective halides 28 and 29. Thereafter these compounds are treated with'acid or base to prepare the halo products hereof E and F. Compounds 28 and 29 can also be treated with butyl lithium, tributyl boron, and hydrogen peroxide in base to the corresponding hydroxy compound and its separable oxo tautomer represented by compounds E and F respectively, which correspond respectively to compounds represented by Formulas E and F above wherein R and R are each hydroxy. These latter compounds are then treated with sodium hydride; thence with an alkyl halide, allyl halide, or acyl halide to prepare the compounds represented by Formulas E and F which correspond respectively to the compounds of Formulas E and F wherein R and R are each alkyloxy, allyloxy, or carboxylic acyloxy.

The use of d or 1 glycidol or d or 1 glycidol tosylate in lieu of epibromohydrin in the foregoing reactions provide for an asymmetric center in the side chain of the molecule. in addition, the compounds of the present invention exhibit geometric isomerism due to chirality of the bridgehead in the annulene ring system.- Each of the isomers resulting from asymmetric carbon atoms and/or chirality and mixtures thereof are included within the scope hereof. These isomers can be separated by conventional means such as by forming salts of the amines and thereafter separating the diastereomeric salts by fractional crystallization followed by regeneration of the free amine. These salts may also be used as the compounds of the present invention as described above. Examples of such salts are the hydrochloride, mesotartrate, sulfate, and maleate.

In the case of the unsubstituted ring compounds of the present invention, the annulene nucleus can be resolved by the following, representative procedure. The unsubstituted annulene compound can be acetylated at the 2 position and thereafter converted to the 2- carboxy compound as a d,l mixture. The cinchonidine salt of the d,l-mixture can be prepared and the diastereomeric salts can be separated by fractional crystallization. Either of the regenerated isomers can then be converted to the corresponding Z-hydroxy compound by treatment sequentially with methyl lithium, Baeyer- Villiger oxidation, and base hydrolysis. Alternatively, the Z-hydroxy compound can be prepared by treating the carboxy compound via a Curtis degradation to give the amino compound followed by acid hydrolysis in aqueous medium. The 2-hydroxy compound can be elaborated to the side chain possessed by the compounds of the present invention as set forth above using d or 1 glycidol tosylate depending upon which isomer is desired.

The terms alkyl and alkenyl, however qualified in the present invention by way of carbon atom limitation or the term lower, refer to straight or branched chain acyclic aliphatic hydrocarbon groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and various isomers thereof. Similarly, the term cycloalkyl" refers to a similar but cyclic group. The term carboxylic acyloxy refers to substituted or unsubstituted acyloxy groups conventionally employed in the pharmaceutical art, preferably the hydrocarbon acyloxy groups. Examples of such are acetate, propionate, butyrate, trimethylacetate, valerate, methylethylacetate, caproate, t-butylacetate, 3-methylpentanoate, enanthate, caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, diphenyl-acetate, cyclopentylpropionate, methoxyacetate, aminoacetate, diethylaminoacetate, trichloroacetate, B-chloropropionate, bicyclo[2.2.2]octane-l-carboxylate, and adamantoate.

Certain of the compounds hereof which are useful as intermediates in the preparation of the compounds of the present invention are novel. Thus, for example, by reference to the foregoing Sequences, the compounds of the formulas 5,6,l8,( l 8'), and 22 are novel intermediates of the present invention.

The following examples further illustrate the method by which the compounds of the present invention of Formula A are prepared.

EXAMPLE 1 1,6-Methano-[l01annulene (1.0 gram) is refluxed in 20 ml. of benzene containing five grams of lead tetraacetate for six hours. The solution is cooled, washed with water, filtered, dried and evaporated. The residue, after evaporation is chromatographed on silica gel to yield 2,5-diacetoxy-2,5-dihydro-l ,6-methane- [l]annulene.

The diacetate (1.0 gram) is heated at 85C. in ml. of glycidol for four hours. Excess glycidol reactant is removed under vacuum and the residue is chromatographed on silica gel to yield 2,5-di-(2,3-oxidoprop-lyloxy)-2,5-dihydro-l,6-methano-[l01annulene and 2- The resultant suspension is filtered through Celite and the filtrate is evaporated to prepare the 2-(2,3- oxidopropl -yloxy)-l,6-methano-[ l0]-annulene prodnet.

The 2-(2,3-oxidoprop-l-yloxy)-l,6-methano- [l0]annulene compound prepared as described above (200 mg.) is dissolved in a mixture of 5 ml. of methanol and 5 ml. of isopropylamine. The resultant mixture is allowed to stand at room temperature for six hours. After this time, the solution is evaporated to dryness under vacuum to produce the 2-(2-hydroxy3- isopropyl-aminopropl -yloxy )-l ,6-methano- [l0]annulene product.

EXAMPLE 2 One gram of 2,5-diacetoxy-2,S-dihydro- [l0]annulene in 5 ml. of glycidol containing 20 mg. of p-toluenesulfonic acid is heated to and maintained at l- 00C. for 16 hours. After this time, the resultant solution is cooled and the cooled mixture diluted with ether and washed with dilute aqueous sodium bicarbonate and is then dried and evaporated to give 2-(2,3- oxidopropl -yloxy)-l ,6-methano-[ l0]annulene which can be further purified by chromatography or vacuum distillation.

The compound prepared as described in the foregoing paragraph is converted to the corresponding 2-(2- hydroxy-3-isopropylaminopropl -yloxy)annulene compound in accordance with the procedure set forth in the last paragraph of Example 1.

EXAMPLE 3 To a solution of l,6-difluoromethano-[ l0]annulene (1.0 gram) in 8 ml. of carbon tetrachloride are added 0.9 grams of bromine in 3 ml. of carbon tetrachloride. The resultant mixture is stirred at room temperature for 1 hour after which time it is cooled to 0C., filtered and the residue dried under vacuum to prepare the 2,5- dibromo-2,5-dihydro-1,6-difluoromethano- [l0]annulene product.

The 2,5-dibromo-2,5-dihydro-l,6-difluoromethano- [l0]annulene (l.0 gram) in 2 ml. of glycidol and 0.3 grams of dihydropyran is heated to C. and maintained thereat for one hour. After this time, the mixture is cooled and then diluted with ethyl acetate. The diluted solution is washed with water, dried and evaporated. The residue is chromatographed to prepare the 2,5-di(2,3-oxidopropl -yloxy)-2,5-dihydro-l ,6 difluoromethano-[l0]annulene and 2-(2,3-oxidopropl-yloxy)-1,6-difluoromethano-[ l0]annulene compounds.

The two compounds prepared as described in the foregoing paragraph are treated as set forth in Example 1, paragraphs 4 and 5 to prepare the 2-(2-hydroxy-3- isopropylaminopropl -yloxy)- l ,6-difluoromethano- [l0]annulene product.

EXAMPLE 4 The procedure described in the last paragraph of Example above is repeated using, as starting compounds, each of 2-(2,3-oxidoprop-l-yloxy)l,6- methano-[ l0]annulene and 2-(2,3-oxidoprop-lyloxy)-l ,6-difluoromethano-[ l0]annulene with each of the reactants set forth under column A below to respectively prepare those products set forth under Column B below.

methylamine diethylamine diisopropylamine pentylamine octylamine t-butylamine phenethylmethylamine cyclohexylamine cyclopropylamine cyclooctylamine benzylamine dibenzylamine 2-(2-hydroxy-3-mthylaminopropl -yloxy)-l ,6- methano-[ l]-annulene,

2-( 2-hydroxy-3-methylaminopropl -yloxy)- l ,6-

difluoro-methano-[ l0]annulene,

2-(2-hydroxy-3-diethylaminopropl -yloxy)-l ,6-

methano-[ l0]annulene,

2-(2-hydroxy-3-diethylaminoprop-1-yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-diisopropylaminoprop-l -yloxy)-l ,6-

methano[ l0]annulene,

2-( 2-hydroxy-3-diisopropylaminoprop-l -yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-(2-hydroxy-3-pentylaminoprop-1-yloxy)-l,6-

I methano-[l01-annulene,

2-(2-hydroxy-3-pentylaminoprop-1-yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-octylaminopropl -yloxy )-l ,6-

methano-[ l0]-annulene,

2-( 2-hydroxy-3-octylaminopropl -yloxy)-l ,6-

difluoromethano-[ l0]annulene,

2-(2-hydroxy-3-t-butylaminoprop-1 -yloxy)-l ,6-

methano-[ l0]annulene,

2-(2-hydroxy-3-t-butylaminopropl -yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-(phenylbut-3-ylamino)-propl yloxy)-l ,6-methano-l l0]annulene,

2-(2-hydroxy-3-(phenylbut-3-ylamino)-propl yloxy)-1 ,6-difluoromethano-[ l0]annulene,

2-(2-hydroxy-3-cyclohexylaminopropl -yloxy)-l ,6-

methano-[ l0]annulene,

2-(2-hydroxy-3-cyclohexylaminoprop-l-yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-(Z-hydroxy-3-cyclopropylaminoprop-l-yloxy)-1,6-

methano-[ l0]annulene, v

2-(2-hydroxy-3-cyclopropylaminopropl -yloxy )-l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-cyclooctylaminopropl -yloxy)-l ,6-

methano-[ l0]annulene,

2-( 2-hydroxy3-cyclooctylaminopropl -yloxy l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-benzylaminopropl -yloxy )-l ,6-

methano-[ l0]ann'ulene,

2-( 2-hydroxy-3-benzylaminopropl -yloxy)-l ,6-

difluoro-methano-[ l0]annulene,

2-( 2-hydroxy-3-dibenzylaminopropl -yloxy)- l ,6-

methano-[ l0]annulene, and

2-( 2-hydroxy-3-dibenzylaminopropl -yloxy)-l ,6-

difluoro-methano-[ l0]annulene.

The following examples further illustrate the method by which the compounds of the present invention of Formulas B and C are prepared.

EXAMPLE 5 Z-Methylnaphthalene (1.0 gram) is dispersed in 5 ml. of diethylether ad to the resulting solution is added 20 ml. of liquid ammonia and 3 ml. of ethanol. 2.0 grams of sodium are added in small portions and the mixture maintained at reflux (34C.) for a period of four hours. After this time, excess sodium is destroyed by the addition of water and the resultant solution evaporated to dryness. The residue is dissolved in n-hexane and the solution washed with water, dried and evaporated to give 2-methyl-l,4,5,8-tetrahydronaphthalene.

2-Methyl-l,4,5,8-tetrahydronaphthylene (0.5 gram) is dissolved in 25 ml. of etherzbenzene (1:1) and to the resultant solution are added 5.0 grams of zinc dust, 2.5 grams of cuprous chloride, and 2.5 grams of methylene iodide. The resultant mixture is reflected until aliquots indicate all starting material is used. Saturated aqueous ammonium chloride (1 ml.) and 50 ml. of hexane are then added. The organic layer is separated, washed with water and dried to give 3-methyltricyclo[4.4.l.0 ]undeca-3,8-diene, obtained by chromatography on silver nitrate impregnated silica gel plates.

2-Methyl-l ,4,5,S-tetrahydronaphthalene (0.5 g.) is dissolved in 10 ml. of diglyme and the resultant solution refluxed while sodium chlorodifluoroacetate (2 equivalents) in 10 ml. of diglyme is added slowly to the diglyme solution with stirring. The resultant solution is cooled, and poured into water. The mixture is extracted with ether and ether extracts dried and evaporated to provide 1 1,1 l-difluoro-3- methyltricyclo[4.4.1.0"]undeca-3,8-diene, obtained by chromatography.

3-Methyltricyclo[4.4. l .0 "]undeca-3 ,8-diene (1.0 g.) in 40 ml. of dioxane containing 7.5 grams of dicyanodichloro-benzoquinone (DDQ) is refluxed for 48 hours. After this time, the solution is cooled and diluted with 200 ml. of ether. The resultant mixture is passed through a column containing 20 grams of neutral alumina and eluted with ether. The eluent is evaporated to provide 3-methyl-l ,6-methano-[ lol-annulene.

In a similar manner, the foregoing method can be practiced with l l ,l 1-difluoro-3-methyltricyclo- [4.4.l.0"]-undeca-3,8-diene to obtain 3-methyl-l,6- difluoromethano-[ l0]annulene.

3-Methyl-l,6-methano-[l0]annulene (500 mg.) is refluxed in 20 ml. of benzene containing lead tetraacetate (2.0 grams) for 2 hours. After this time, the solution is cooled and poured into water. The aqueous solution is extracted with ether and the extracts washed with water, dried and evaporated. The residue is refluxed in 20 ml. of benzene containing p-toluenesulfonic acid (20 mg.) for three hours. The solution is then cooled, washed with water, dried and evaporated to provide 2-acetoxy-3-methyl-l ,6-methano-[ l0]- annulene and 2-acetoxy-4-methyll ,6-methanol0]annulene which are separated by chromatography.

In a similar manner, 2-acetoxy-3-methyl-l,6- difluoro-methano-[l0]annulene and 2-acetoxy-4- methyl-l,6-difluoro-methano-ll0]annulene are prepared.

2-Acetoxy-3-methyll ,6-methano-[ l0]annulene mg.) is dissolved in 5 ml. of ether and to the resultant mixture is added 50 mg. of lithium aluminum hydride. The resultant mixture is stirred for 30 minutes and then 0.5 ml. of methanol is added. Excess aqueous sodium dihydrogenphosphate is then added and the ethereal layer is separated, washed, dried and evaporated. The residue is dissolved in dimethyl-formamide (2 ml.) and 1 equivalent of sodium hydride is added thereto. The resultant solution is warmed briefly to 60C. and then 0.2 ml. of epibromohydrin is added and the resultant mixture heated to 80C. and maintained thereat for two hours. The mixture is then cooled, diluted with water, and extracted with ether. The ether extracts are washed, dried and evaporated to provide 2-(2,3-oxidoprop-l -yloxy)-3-methyl-l ,6-methano- [l] annulene. which can be further purified by chromatography.

In a similar manner, 2-(2,3-oxidoprop-l-yloxy)-4- methyl-l ,6-methano-[ ]annulene, 2-(2,3-oxidopropl -yloxy)-3-methyl-1 ,6-difluoromethano-[ 10]annulene, and 2-(2,3-oxidopropl -yloxy)-4-methyl-1 ,6- difluoromethano-[l0]annulene are prepared in accordance with the foregoing procedure.

The foregoing compounds are treated in accordance with the procedure set forth in the last paragraph of Example l and the procedures of Example 4 to prepare the corresponding N-substituted and N,N-disubstituted amine compounds, for example, 2-(2-hydroxy-3- isopropylaminopropl -yloxy )-3-methyll ,6-methano- [l0]annulene,2-(2-hydroxy-3-t-butylaminoproplyloxy)-3-methyi-1 ,6-methano-[ 10]annulene, hydroxy-3-isopropylaminopropl -yloxy )-4-methyl-l ,6- methano-[ 10]annulene, 2-(2-hydroxy-3-tbutylaminoprop-lyloxy)-4-methyl-1,6-methano- [10]annulene, 2-(2-hydroxy-3-isopropylamino-proplyloxy)-3-methyl-1,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3-t-butylaminoprop-l.yloxy)-3-methyll,6-difluoro-methano-[10]annulene, 2-( 2-hydroxy-3- isopropylaminopropl -yloxy)-4-methyl-l ,6- difluoromethano-[10]annulene, and 2-(2-hydroxy-3-tbutylaminoprop- 1 -yloxy)-4-methyl-l ,6-difluoromethano[ l0]-annulene.

In like manner, the foregoing procedures of this example can be practiced upon other 2-substituted naphthalene starting materials such as 2-allylnaphthalene, 2- ethylnaphthalene, Z-n-propylnaphthalene, and Z-isopropylnaphthalene, to prepare the corresponding 3 (or 4)-substituted (allyl, ethyl, n-propyl, isopropyl, and so forth) compounds in the 2-(2-hydroxy-3- monosubstituted or disubstituted aminoprop-l-yloxy)- 1,6-methano or 1,6-difluoromethano-[10]annulene series, for example,

2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-3- ethyl-1,6-methano-[ 10]annulene,

2-( 2-hydroxy-3-isopropylaminopropl -yloxy)-4- ethyl-l ,6-methano-[ 10]annulene,

2-( 2-hydroxy-3-t-butylaminopropl -yloxy)-4-ethyll,6-methano-[10]annulene,

2-( 2-hydroxy-3-isopropylaminopropl -yloxy)-3- ethyl-1,6-difluoromethano-[ 10]annulene, 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-4- ethyl-l ,6-difluoromethano-[ 10]annulene, 2-(2-hydroxy-3-isopropylaminopropl -yloxy)-3- allyl-1 ,6-methano-[ 10]annulene,

2-( 2-hydroxy-3-t-butylaminopropi -yloxy )-3-allyll ,6-methano-[ 10]annulene, 2-(2-hydroxy-3-isopropylarninopropi -yloxy )-4- allyl-1 ,6-methano-[ 10]annulene,

2-( 2-hydroxy-3-t-butylaminopropl -yloxy )-4-allyll,6methano-[10]annulene,

2-( 2-hydroxy-3-isopropylaminopropl -yloxy)-3 allyl-l ,6-difluoromethano-[ 10] annulene,

2-( 2-hydroxy-3-t-butylaminopropl -yloxy)-3-allyll,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-4- allyl-1,6difluoromethano-[10]annulene, 2-( 2-hyd roxy-3-t-butylaminopropl -yloxy )-4-allyli,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3isopropylaminoprop-l-yloxy)-3- isopropyl-l,6-methano-[10]annulene, 2-(2-hydroxy-3-isopropylaminopr0p-l -yloxy)-4- isopropyl-l,6-methano-[10]annulene, 2-( 2-hydroxy-3-t-butylaminopropl -yloxy )-4- isopropyl-l,6-methano-[10]annulene, 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-3- isopropyl-l,6-difluoromethano-[10]annulene, 2-( 2-hydroxy-3-isopropylaminopropl -yloxy)-4 isopropyl-l,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3-dimethylaminoprop-l-yloxy)-3-npropyl-l ,6-methano-[ l01annulene, 2-(2-hydroxy-3-dimethylaminoprop-l-yloxy)-4-npropyl-l ,6-methano-[ 10]annulene, 2-(2-hydroxy-3-dimethylaminoprop-1-yloxy)-3 -npropyl-l ,6-difluoromethano-[l0lannulei1e. 2-(2-hydroxy-3-dimethylaminoprop-l-yloxy)-4-npropyl-l,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3-dibenzylaminoprop-l-yloxy)-3- ethyl-l,6-methano-[10]annulene, 2-(2-hydroxy-3-t-butylaminopropl -yloxy )-3-ethyll,6-methano-[10]annulene, 2-( 2-hydroxy-3 -dibenzylaminoprop-l -yloxy )-4- ethyl-l,6-methano-[10]annulene, 2-(2-hydroxy-3-dibenzylaminoprop-l -yloxy)-3- ethyl-l ,6-difluoromethano-[ 10]annulene, and 2-( 2-hydroxy-3-dibenzylaminoprop-l -yloxy )-4- ethyl-1,6-difluoromethano-[ 10]annulene. The following examples further illustrate the method by which the 3-allyl compounds of the present invention represented by Formula B can be prepared.

EXAMPLE 6 2,5-Diacetoxy-2,5-dihydro-l ,6-methano- [10]annulene (prepared in Example I) (1.0 grams) is refluxed in 15 ml. of allyl alcohol for a period of six hours. After this period, excess solvent is removed under vacuum to provide 2,5-diallyloxy-2,5-dihydro-l,6- methano-[l01annulene which can be further purified by chromatography.

The 2,5-diallyloxy-2,5-dihydro-l ,6-methano- [10]annulene compound (500 mg.) is refluxed in 200 ml. of benzene containing p-toluenesulfonic acid (25 mg.) for a period of 2 hours. After this time, the resultant mixture is cooled, and 0.1 ml. of triethylamine is added thereto. The solution is then washed with water, dried and evaporated to give 2-allyloxy-l,6-methano- [10]annulene.

Alternatively, 2,5-diacetoxy-2,5 -dihydro-l ,6- methano-[l01annulene (500 mg.) is refluxed in 15 ml. of allyl alcohol containing 25 mg. of p-toluenesulfonic acid for a period of six hours. After this time, the solution is cooled, and 0.1 ml. of triethylamine are added thereto. The solution is washed with water, dried and evaporated to give 2-allyloxy-l ,o-methano- [10]annulene.

2-Allyloxy-l,6-methano-[10]annulene mg.) is refluxed in 2 ml. of N,N-dimethylaniline under nitrogen for three hours. The solvent is then removed under vacuum and the residue dissolved in ether. The ether solution is washed with dilute hydrochloric acid and then water, dried and evaporated. Chromatography of the residue on silica gel yields 2-hydroxy-3-allyl-l ,6- methano-[ IOI-annulene.

One hundred milligrams of 2-hydroxy-3-allyl-l ,6- methano-[ l]annulene is dissolved in 4 ml. of dimethylformamide and one equivalent of sodium hydride is added to the resultant solution. The mixture is stirred and warmed to 60C. until hydrogen evolution ceases. Epibromohydrin (1.5 equivalents) is then added and the reaction mixture is heated to 80C. for two hours. The solution is then cooled, diluted with ehter, washed with water, dried and evaporated to give 2-(2,3 oxidopropl -yloxy)-3-allyl-l ,6-methano-[ l0]annulene which can be further purified by chromatography.

The compound prepared in the preceding paragraph is treated in accordance with the procedures set forth in the last paragraph of Example 1 hereof and in accordance with the procedures of Example 4 hereof to prepare, for example, 2-(2-hydroxy-3- isopropylaminopropl -yloxy)-3-allyl-l ,6-methanol 0 lannulene, 2-( 2hydroxy-3tbutylaminopropl yloxy )-3-allyl-l ,6-methano-[ l0]annulene, 2-(2- hydroxy-3-methylamino-propl -yloxy)-3-allyll ,6- methano-[ l0]annulene, and so forth.

EXAMPLE 7 2,5-Dibromo-2,5-dihydro-l ,o-difluoromethano- [l0]annulene (prepared as described in Example 3) (1.0 gram) is stirred in 10 ml. of allyl alcohol for 45 minutes. Thereafter, triethylamine (1.0 ml.) and diethylether (50 ml.) are added and the solution washed with water, dried, and evaporated to give 2,5- diallyloxy-2,5-dihydro-1,-difluoro-methano- [l0]annulene which can be further purified by recrystallization from ethcrzhexane.

Alternatively, the 2,5-dibromo-2,5-dihydro-l,6- difluoro-methano-[ l0]annulene (1.0 gram) is refluxed in ally] alcohol 10 ml.) for two hours. The resultant solution is cooled and triethylamine (1.0 ml.) and diethylether (50 ml.) are added. The ethereal soluton is washed with water, dried and evaporated to give 2- allyloxy-l,6-difluoromethano-[ l0]annulene which can be further purified by recrystallization from hexane.

The compound prepared in the preceeding paragraph is treated in accordance winh the procedures of Example 6 (paragraphs 4,5, and 6) to provide the 2-(2-hydroxy-3-substituted -aminoprop-l-yloxy) compounds of the present invention in the 1,6- difluoromethano series, for example, 2-(2-hydroxy-3- isopropylaminoprop-l -yloxy)-3-allyl-1,6-difluoromethano-[10]annulene, 2-(2-hydroxy-3-t-butylaminoprop-l-yloxy)-3-allyl-l ,o-difluoromethano- [l0]annulene, 2-(2-hydroxy-3-diethylaminoprop-lyloxy)-3-allyl-l,6-difluoromethano-[ l0]annulene, and so forth.

The following examples further illustrate the method by which the compounds of the present invention of Formulas D, G, and H are prepared.

EXAMPLE 8 2-(2,3-Oxidoprop-l-yloxy)-5-acetoxy-2,5-dihydro- 1,6-methano-[101annulene (100 mg.) is dissolved in 5 ml. of methanol and to the resultant solution is added 1 equivalent of potassium hydroxide in 0.5 ml. of water. After a period of one hour at room temperature, the solution is poured into water and extracted with diethyl ether. The ether extracts are dried and evaporated to give 2-(2,3-oxidoprop-l-yloxy)-5-hydroxy-2,5-

dihydro-l ,6-methano-[ l0]annulene. The thus prepared compound (100 mg.) is dissolved in 5 ml. of

chloroform and to the resultant solution is added activated manganese dioxide (1.0 g.). The resultant solu- 5 tion is stirred for eight hours at room temperature and then filtered and evaporated to yield 2-(2,3-oxidopropl-yloxy)-5-0xo-2,5-dihydro-l,6-methano- [l0]annulene, and its S-OH tautomer.

2,5-Dibromo-2,5-dihydro-l ,6-difluoromethano- [l0]annulene (prepared as described in Example 3) (200 mg.) is dissolved in a hot solution of sodium acetate (500 mg.) in a minimum volume of acetic acid (ca. 1 ml.). The resultant mixture is stirred at 80C. for one hour. After this time, it is poured into water and extracted with ethyl acetate. The extracts are dried and evaporated to give 2,5-diacetoxy-2,5-dihydro-l,6- difluoromethano-[l0]annulene which can be further purified by recrystallization from chloroformzhexane. The diacetate thus prepared (100 mg.) is dissolved in 5 ml. of methanol and a solution of 2 equivalents of potassium hydroxide in 0.5 ml. of water is added thereto. The resultant mixture is stirred for one hour at room temperature and is then poured into water and extracted with diethyl ether. The ether extracts are dried and evaporated to give 2,5-dihydroxy-2,S-dihydro-l,6- difluoromethano-[l0]annulene which can be further purified by recrystallization from chloroformzhexane. The diol thus prepared (100 mg.) is dissolved in dimethyl-formamide (2 ml.) and 1 equivalent of sodium hydride is added thereto. The resultant mixture is stirred and warmed until hydrogen evolution ceases and then 200 mg. of epibromohydrin are added thereto. The solution is then heated to 80C. for four hours. After this time, water is added and the mixture is extracted with diethyl ether. The extracts are washed with water, dried and evaporated to give 2-(2,3- oxidopropl -yloxy)-5-hydroxy-2,5-dihydro-l ,6- difluoromethano-[l0]annulene. The thus prepared 5- hydroxy compound is then converted to the corresponding 5-oxo compound as described above, thus preparing 2-(2,3-oxido-pro'p-l-yloxy)-5-oxo-2,5- dihydro-l,6-difluoromethano-[l0]-annulene and its S-OH tautomer.

EXAMPLE 9 One hundred milligrams of 2-(2,3-oxidoprop-lyloxy)-2,5-dihydro-5 -oxo-l ,6-methano-[ l0]annulene (or its S-hydroxy tautomer) is dispersed in glyme and to the solution is added one equivalent of potassium tbutoxide. The solution is stirred for 15 minutes and thereafter 0.2 ml. of allyl bromide dispersed in 0.5 ml. of glyme is added thereto. The resultant mixture is stirred for one hour and then water and ether are added. The ethereal solution is dried and evaporated to give a residue which is chromatographed to provide 2- (2,3-oxidopropl -yloxy)-5-allyloxy-l ,6-methano- [l0]annulene.

The compound prepared as described in the foregoing paragraph is treated in accordance with the procedure set forth in the last paragraph in Example 1 to prepare 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-5- allyloxy-l ,6-methano-[ l0]annulene.

' In a similar manner, by following the procedure of Example 4, using the product of the firstparagraph of this example, there are respectively prepared the corresponding substituted amino compounds thereof. Similarly, the foregoing procedures can be practiced upon the corresponding 1,6-difluoromethano compounds to prepare the substituted amino compounds, for example, 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-5- allyloxy-l ,6-difiuoromethano-[ l ]annulene, 2-( 2- hydroxy-3-t-butylaminoprop-l -yloxy )--allyloxy-l ,6- difluoro-methano-[ l0]annulene.

By repeating the above ether preparation procedure using, in lieu of allyl bromide, the other alkyl bromides contemplated by the present invention, that is, ethyl bromide, methyl bromide, propyl bromide and isopropyl bromide, the corresponding S-alkyloxy of one to three carbon atom annulene compounds, both in the l,6-methano and 1,6-difluoromethano series and hearing a 2-(2-hydroxy-3-monosubstituted or di-subtituted aminoprop-l-yloxy)-grouping are prepared.

EXAMPLE l0 2-(2,3-Oxidoprop-1-yloxy)-5-oxo-2,5-dihydro- [l0]annulene (or S-hydroxy tautomer) (100 mg.) is dispersed in 3 ml. of glyme and to the resultant solution is added one equivalent of potassium t-butoxide. The resultant solution is stirred at room temperature for one hour and then one equivalent of acetyl chloride in 0.5 ml. of glyme is added thereto. The resultant mixture is stirred for two hours at room temperature and then water and then diethyl ether are added. The ethereal layer is washed with water, dried and evaporated to give 2-(2,3-oxidoprop-l -yloxy)-5-acetoxy-l ,6- methano-[ l0]annulene.

The compound prepared in the preceding paragraph is treated in accordance with the procedure set forth in the last paragraph of Example 1 and the procedure set forth in Example 4 to prepare the corresponding monosubstituted and disubstituted amino hydroxypropyl compounds, for example, 2-(2-hydroxy-3- isopropylaminopropl -yloxy )-5-acetoxy-l ,6-methano- [l0 ]annulene, 2-( 2-hydroxy-3-t-butylaminopropl yloxy)-S-acetoxy-l ,6-methano-[ l0]annulene, 2-( 2- hydroxy-3-isopropyl-aminoprop-1-yloxy)-5-acetoxyl,6-difluoromethano-[ l0]annulene, 2-(2-hydroxy-3-tbutylaminopropl -yloxy)-5-acetoxy-l ,6-di-fluoromethano-[l0]annulene, and so forth.

In lieu of the use of acetyl chloride in the foregoing procedure, the use of the other carboxylic acyl chlorides of the present invention will prepare the corresponding S-carboxylic acyloxy of up to six carbon atom compounds.

2-(Z-Hydroxy-3-isopropylaminoprop-1-yloxy)-5 acetoxy-[l01annulene (lOO mg.) is dispersed in 5 ml. of tetrahydro-furan and to the resultant solution is added one equivalent of potassium hydroxide in 0.5 ml. of water. The mixture is stirred for one hour at room temperature and then poured into water. The resultant mixture is extracted with ether and the extracts dried and evaporated to give 2-(2-hyroxy-3- isopropylaminoprop-l -yloxy )-5-hydroxy-l ,G-methano- [l0]annulene and its 5-oxo, 2,5-dihydro tautomer.

Similarly, 2-(2-hydroxy-3-t-butylaminoprop-lyloxy)-5-hydroxy-l,6-methano-[ l0]annulene,2-(2- hydroxy-3-isopropyl-aminoprop-l -yloxy)-5-hydroxyl,6-difluoromethano-[ l0]annulene, 2-( 2-hydroxy-3-tbutylaminopropl -yloxy)-5-hydroxy-l ,6-di-fluoromethano-[l01annulene can be prepared.

Two hundred milligrams of 2-(2-hydroxy-3- isopropyl-aminopropl -yloxy )-5-acetoxyl ,o-methano [l0]annulene is refluxed in 5 ml. of acetone for hours. The solvent is then removed under vacuum to give 22 2-(2,2-dimethyl3-isopropyl-5-oxazolidinyl-methoxy)- 5-acetoxy-l ,6-methano-[ lOl-annulene.

To the compound thus prepared (200 mg.) in 20 ml. of ether are added 2 equivalents of lithium aluminum hydride. The result mixture is stirred for 30 minutes and 1 ml. of water is added. The ethereal solution is then washed with water, dried and evaporated to give the 2-(2,2-dimethyl-3-isopropyl-5-oxazolidinylmethoxy)-5-oxo-2,5-dihydro-l ,6-methano- [l0]annulene or its S-OH tautomer dihydroisomer.

To the compound prepared as above described (100 mg.) in 20 ml. of diethyl ether is added one equivalent of methyl magnesium iodide. After 30 minutes, a few drops of sodium dihydrogen phosphate are added and the mixture is stirred for 15 minutes. The ethereal layer is then separated dried and evaporated to give a residue which is dissolved in 1 ml. of pyridine. To the resultant mixture is added 0.4 ml. of phosphorus oxychloride and the resultant mixture is then heated to C. for one hour. The mixture is then cooled and after cooling poured into water. The product is extracted with ether and ether extracts being dried and evaporated to give the corresponding 2-(2,2dimethyl-3-isopropyl-5- oxazolidinyl methoxy )-5-methyl-l ,6-methano-[ l0 annulene.

The compound thus prepared mg.) is stirred in 5 ml. of aqueous ethanolic hydrochloric acid for one hour. The mixture is then made alkaline with aqueous sodium hydroxide and the resultant mixture extracted with ether. The ether solution is dried and evporated to give 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)-5- methyl-l ,6-methano-[ l0]annulene.

In a similar manner, 2-( 2-hydroxy-3-isopropyla.minopropl -yloxy)-5-methyll ,o-difluoromethano- [l0]annulene, 2-( 2-hydroxy-3-t-butylaminopropl yloxy)-S-methyl-l ,6-difluoromethano-[ l0]annulene is prepared.

By repeating the above procedure whereby the alkyl group is introduced into the C5 position employing, in lieu of methyl magnesium iodide, the other alkyl of one to three carbon atom magnesium iodides or the alkenyl of two to three carbon atom magnesium iodides, the corresponding 5-alkyl and alkenyl compounds bearing a 2-(2-hydroxy-3-isopropylaminoprop-lyloxy) group both in the l,6-methano and 1,6- difluoromethano series are prepared. In a similar manner, by use of the selective procedures of Example 4, the corresponding mono-substituted compounds are prepared in the 5-alkyl and alkenyl series. The disubstituted amine compounds are prepared in accordance with the procedure of Example 19, infra.

EXAMPLE 1 1 One hundred milligrams of 2-(2,3-oxidoprop-lyloxy )-5-oxo-2,5-dihydro-l ,6-methano-[ l0]annulene in 2 ml. of chloroform is added to a solution of 1.] equivalents of catecholphosphotrichloride in 2 ml. of chloroform. The resultant mixture is left for one hour at room temperature and thereafter 0.5 ml. of triethylamine is added. The mixture is filtered through 5 grams of silica gel and the filtrate evaporated to give 2-(2,3- oxidoprop-1-yloxy)-5-chloro-l ,6-methanol0]annulene which can be further purified by chromatography.

EXAMPLE 12 Upon substitution of epibromohydrin for allyl bromide in the procedure of paragraph l of Example 9, there is prepared the 2,5-di-(2,3-oxidoprop-l-yloxy)- l,6-methano-[l]annulene, or the corresponding 1,6- difluoromethano compound when employing the appropriate starting compound.

By treatment of the digylcidol ether with one equivalent of the amine as set forth in the procedure of the last paragraph of Example 1, and the procedures of Example 4, there is prepared, for example, 2-(2-hydroxy- 3-dimethylamino-prop-l-yloxy)-5-(2,3-oxidoprop-lyloxy)-l ,6-methano-[ l0]-annulene, 2-(2-hydroxy-3- isopropylaminoprop-l-yloxy)-5-(2,3-oxidoprop-lyloxy)-l ,6-methano-[ l0]annulene,2-(2-hydroxy-3-tbutylaminoprop-l-yloxy)-5-(2,3-oxidoprop-l-yloxy)- l,6-methano-[ l0]annulene.

By employing two equivalents of the amine in accordance with the procedure of the last paragraph of Example l and the procedures of Example 4, there is prepared, for example, 2,5-di-(2-hydroxy-3- isopropylaminopropl -yloxy )-l ,6-difluoro-methano- [l0]annulene,2,5-di-( 2-hydroxy-3-t-butylaminopropl-yloxy)-l ,6-difluoromethano-[ l0]annulene.

EXAMPLE 13 One hundred milligrams of 2-(2,3-oxidoprop-lyloxy)-5-(2-hydroxy-3-isopropylaminoprop-l -yloxy)- l,6-methano-[ l0]annulene in 2 ml. of pyridine is addd a solution of one equivalent of acetic anhydride in 0.5 ml. of pyridine at room temperature. The resultant mixture is stirred for 24 hours and then poured into water. The aqueous solution is extracted with chloroform and the chloroform extracts separated, washed with water, dried and evaporated to give 2-(2,3-oxidoprop-lyloxy)-5-(2-hydroxy-3-is0propyl-acetylaminoprop-l yloxy)-l ,6-methano-[ l0]annulene.

In like manner, the other mono-substituted amino compounds can be treated in accordance with this procedure to provide the corresponding N-acetyl com pounds.

The roduct of the foregoing paragraph, if treated in accordance with the procedure of the last paragraph of Example I or the procedures of Example 4, can be converted to the corresponding ring opened aminohydroxypropyl compound, for example, 2-(2-hydroxy-3- isopropylaminopropl -yloxy )-5-( 2-hydroxy '3- isopropylacetylaminoprop-l -yloxy)-l ,6-methano- [l0]annulene, 2-( 2-hydroxy-3-t-butylaminopropl yloxy )-5 -(2-hydroxy-3-isopropylacetylaminopropl yloxy)-l ,6-methano-[ l0]annulene, 2-(2-hydroxy-3- isopropylaminoprop-l-yloxy)-5-(2-hydroxy-3-tbutylacetylaminoprop-l -yloxy)-l ,-methano- [l0]annulene, 2-(2-hydroxy-3-t-butylaminoprop-l yloxy )-5 2-hydroxy-3 -t-butylacetylaminopropl yloxy)-l ,6-methano-[ l0]-annulene,

EXAMPLE 14 The procedure of the first paragraph of Example 9 is repeated, using, in lieu of ally bromide, ethyl chloroformate to provide the 2-(2,3-oxidoprop-l-yloxy)-5- ethoxycarbonyloxy-l ,6-methano-[l01annulene product.

The product thus obtained (200 mg.) is dissolved in 5 ml. of ethanol containing isopropylamine (1.1 equivalent) and the resultant solution is allowed to stand at room temperature for one hour. Excess ethanolic methylamine is then added and the mixture left at room temperature for 48 hours. Excess solvent is then removed under vacuum to give the 2-(2-hydroxy-3- isopropylaminoprop-l-yloxy(-5-(N- methylcarbamyloxy)-l ,6-methano-[ l0]annulene. Also prepared likewise is 2-(2-hydroxy-3-t-butylaminopropl -yloxy)-5 N-methylcarbamyloxy )-l ,G-methano- [l0]annulene. Similarly, upon substitution of the latter part of the above procedure of an alternate amine in lieu of methyl amine, there is prepared the corresponding S-(carbamyl, N-lower alkyl-carbamyloxy, and N,N- di lower alkylcarbamyloxy) compounds, both in the l,6-methano and l,6-difluoromethano series, for example, 2-( 2-hydroxy-3-n-octylaminoprop-l -yloxy)-5- (N ,N-dimethylcarbamyloxy l ,6-difluoromethano- [l0]annulene, and so forth.

EXAMPLE 15 Two hundred milligrams of 2-(2,3-oxidoprop-lyloxy)-l,6-methan-[l0]annulene in 0.5 ml. of acetic anhydride is added to a solution of 250 milligrams of cupric nitrate trihydrate in 2 ml. of acetic anhydride at 0C. The resultant mixture is stirred for 10 minutes and then poured into 200 ml. of ether. The ethereal solution is filtered and evaporated to dryness under high vacuum to provide the 2-(2,3-oxidopro'p-l-yloxy)-5- nitro-l,6-methano-[ l0]annulene which can be further purified by chromatography.

By treatment thereof according to the procedures of Example I (last paragraph) and 4, 2-(2-hydroxy-3- isopropyl-aminopropl -yloxy)-5-nitrol ,6-methano- [l0]annulene. Also prepared are 2-(2-hydroxy-3-tbutylaminoprop-l -yloxy)-5-nitro-l ,6-methano- [l0]annulene and 2-(2-hydroxy-3-isopropylaminopropl -yloxy)-5-nitrol ,6-difluoromethano- [l0]annulene and 2-(2-hydroxy-3-t-butylaminoprop-1- yloxy)-5 -nitrol ,6-difluoromethano-[ l0]annulene.

2-(2,3-Oxidoprop-l -yloxy )-5-nitro-l ,G-methano- [l0]annulene mg.) is hydrogenated in ethyl acetate (5 ml.) containing 5 percent palladium on carbon (50 mg.) until the theoretical volume of hydrogen has been absorbed. The solution is then filtered and evaporated to yield 2-(2,3-oxidoprop-l-yloxy)-5-amino-l,6- methano-[ l0]annulene.

The S-amino compound prepared as described above is treated in accordance with the last paragraph of Example l or in accordance with the procedures of Example 4 above to prepare the corresponding 2-(2- hydroxy-3-monosubstituted or disubstituted aminoprop-l-yloxy) compounds, both in the l,6-methano and l,6-difluoromethano series, for example, 2-(2- hydroxy-3-isopropylaminoprop-I -yloxy )5-amino-l ,6- difluoromethano-[ l0]annulene, 2-(2-hydroxy-3-tbutylaminoprop-l -yloxy)-5-amino-l ,6-difluorome- 25 thano-[ l]annulene, 2-(2-hydroxy-3- isopropylaminopropl -yIoxy)--amino-l ,6-methano- [l0]annulene, 2-(2-hydroxy-3-t-butylaminopropi yloxy)-5-amino-l,6-methano-[l0]annulene, and so forth To 250 mg. of 2-(2,3oxidoprop-l-yloxy)-5-amino- 1,6-methano-[l01annulene in 3 ml. of triethylamine is added 1.1 equivalent of acetic anhydride at room temperature. The resultant mixture is left at room temperature for one hour and then poured into water. The product is extracted with ether, the ether extracts being washed with dilute hydrochloric acid, and then water, dried and evaporated to give 2-(2,3-oxidoprop-1- yloxy )-5 -acetamido-1 ,6-methano-[ 1G l-annulene.

By employing alternate carboxylic acid anhydrides in lieu of acetic anhydride in the above procedure, (cf. Example the corresponding S-acyl substituted amino compounds are prepared.

The foregoing acyl substituted amino compounds can be treated in accordance with the procedure of the last paragraph of Example 1 or the procedures of Example 4' to prepare the corresponding 2-(2-hydroxy-3- monosubstituted or di-substituted aminoprop-l-yloxy) compounds, for example, 2-(2-hydroxy-3- isopropylaminopropl -yloxy)-5-acetamido-l ,6- methano-[ l0]annulene, 2-(2-hydroxy-3-tbutylaminopropl -yloxy)-5-acetamido-l ,6-methano- [l0]annulene, 2-(2-hydroxy-3-iso-propylaminoprop- 1-yloxy)-5-acetarnido-1 ,fi-difiuoromethano- [l0]annulene, and 2-(2-hydroxy-3-t-butylaminopropl-yloxy)-5-acetamido-l ,6-difluoromethano- [l0]annulene, and 2-(2-hydroxy-3-dipentylaminopropl-yloxy)-5-propionamido-l ,6-methano-[ l0]annulene, and so forth.

Upon substituting methanesulfonyl chloride in place of acetic anhydride in the procedure of paragraph 4 of this example, the corresponding S-mesylamino compound can be prepared and further elaborated at the C2 position, as above discussed, to prepare the corresponding S-mesylamino compounds of the present invention, e.g., 2-(2-hydroxy-3-isopropylamino-propl-yloxy)-5-mesylamino-l ,6-methano-[ l0]annulene, 2-(Z-hydroxy-3-t-butylaminoprop-i-yloxy)-5- mesylamino-1 ,6-methano-[ l0]annulene, hydroxy-3-isopropylaminopropl -yloxy )-5- mesylamino-l,6-difluoromethano-[l0]annulene, 2-(2- hydroxy-3-t-butylaminoprop-l-yloxy)-5-mesylaminol,6-difluoromethano-[ l0]annulene, and so forth.

2-(2,3-Oxidopropl -yloxy)-5-aminol ,G-methano- [101-annulene (200 mg.) is refluxed in ethyl formate (10 ml.) for eight hours. The bulk of the solvent is then removed by distillation and the residue evaporated to dryness to give 2-(2,3-oxidoprop-l-yloxy)5- formamido-l ,6-methano-[ IOI-annulene.

The foregoing S-formamido compound can be elaborated at the C-2 position as discussed above to prepare the corresponding S-formamido compounds of the present invention, for example difluoromethano-[ l0]annulene, and so forth.

Two hundred milligrams of 2-(2,3-oxidoprop-lyloxy)-5-aminol ,6-methano-[ l0]annulene is stirred in 10 ml. of isopropanol containing 500 mg. of sodium carbonate and Ll equivalent of benzyl chloride for seven days at room temperature. The resultant mixture is then poured into water and extracted with ether. The ethereal solution is dried and evaporated to give 2-(2,3-

2-( 2-hydroxy-3- ethylaminopropl -yloxy)-5-formamido-i ,6-

oxidoprop- 1 -yloxy )-5-benzylamino-l ,6-methano- [l0]annulene.

Upon substitution of alternate alkyl or alkenyl chlorides in lieu of benzyl chloride in the above procedure, the corresponding S-alkyl amino, and alkenyl amino compounds can be prepared.

To 250 mg. of 2-(2,3-oxidoprop-l-yloxy)-5-amino- 1,6-methano-[l01annulene in 3 ml. of triethylamine is added 1.1 equivalent of ethyl chloroformate at room temperature. The resultant mixture is left at room temperature for one hour and then poured into water. The product is extracted with ether, the ether extracts being washed with dilute hydrochloric acid, and then water, dried and evaporated to give 2-(2,3-oxidoprop-lyloxy)-5-ethoxycarbonylamino-1,6-methano- [l0]annulene.

in like manner, by use of other alkyl chloroformates hereof, the corresponding S-alkoxycarbanylamine compounds are prepared.

Upon heating 2-(2,3-oxidoprop-l-yloxy)-5- ethoxycarbonylamino-l ,6-methano-[ l0]annulene in 1 ml. of dimethylamine and 10 mls. of tetrahydrofuran for two hours at reflux followed by evaporation to dryness, 2-(2,3-oxidoprop-l-yloxy)-5-(N,N-dimethylcarbamylamino)-l ,6-methano-[ l0]annulene is prepared. in like manner, the other N,N-

dimethylcarbanylamino compounds hereof and, by substitution of methyl amine and ammonia for dimethylamine, the other N-methylcarbamylamino and carbamylamino compounds hereof are prepared.

The foregoing prepared compounds of the 5- benzylamino, -alkylamin0, -alkenylamino, alkoxy carbonylamino, N,N-dimethyl-carbamylamino, N- methylcarbanylamino, or carbamylamino series are elaborated at the C2 position as discussed above to prepare the corresponding CS substituted compounds for example 2-(2-hydroxy-3- isopropylaminoprop-1-yloxy)-5-ethyl-amino-1,6- methano-[l0]annulene, 2-(2-hydroxy-3-t-butylaminoprop-1-yloxy)-5 ethylamino- 1 ,6-methano- {l0]annulene, and so forth.

Thus prepared, for example, are 2-(2-hydroxy-3- isopropyl-aminopropl -yloxy)-l ,6-methano-5- methoxycarbonylamino-[l0]annulene; 2-(2-hydroxy- 3-t-butylaminopropl -yloxy)-l ,6-methano-5- methoxycarbonylamino-[l0]annulene; 2-(2-hydroxy- 3-isopropylaminopropl -yloxy)-l ,6-difluoromethano- 5-methoxy-carbonylamino-[ l0]annulene; 2-(2- hydroxy-3-t-butylaminopropl -yloxy)- l ,6- difluoromethano-S-methoxycarbonylamino- [l0]annulene; 2-(2-hydroxy-3-isopropylaminopropl yloxy)-l ,6-methano-5carbamylamino-[ l0]annulene; 2-(2-hydroxy-3-t-butyl-aminoprop-1-yloxy)-1,6- methano-S-carbamylamino-[ l0]annulene; hydroxy-3-isopropylaminoprop-1-yloxy)-l ,6- difluoromethano-S-carbamylamino-[ l0]annulene; and 2-(2-hydroxy-3-t-butylamino-propl -yloxy)-l ,6- methano-S-carbamylamino-[ l0]annulene.

Also prepared in accordance with the methods hereof, cf. Example 4, is, for example 2-(2-hydroxy-3- (i-morphlino)-prop-l -yloxy)-l ,o-methano- [l0]annulene and 2-(2-hydroxy-3-amino-prop-lyloxy)-l,6-methano-[l0]annulene, and the corresponding compounds in the 1,6-difluoromethano series.

The following examples further illustrate the manner by which the compound of the present invention represented by Formulas l5 and F can he prepared.

EXAMPLE 16 2,5-Diacetoxy-2,5-dihydro-1,6-methano- [l]annulene (500 mg.) is dissolved in 20 ml. of chloroform and a solution of 1 molar equivalent of bromide in 10 ml. of chloroform is added thereto. After the bromine color has faded, the solvent is evaporated to give 2,5-diacetoxy-7, 10-dibr0mo-2,5 ,7,10-tetrahydro-1,6- methano-[ l0]annulene.

In a similar manner, 2,5-diacetoxy-7,10-dibromo- 2,5 ,7,l0-tetrahydro-1 ,6-difluoromethano- [l0]annulene is prepared.

One hundred milligrams of 2,5-diacetoxy-7,l0- dibromo-2,5,7,IO-tetrahydro-1,6-methano- [l0]annulene is disoolved in 2 ml. of dimethylformamide and 1.1 equivalents of diazabicyclononene is added thereto. The resultant solution is refluxed for 24 hours and then 5 ml. of dilute hydrochloric acid is added thereto. The solution is extracted with ether and the ether extracts are dried, and evaporated to give a residue which is chromatographed to provide 2- acetoxy-7-bromo-l,6-methano-[l0]annulene and 2- acetoxy-lO-bromo- 1 ,6-methano-[ [l0]annulene.

By employing chlorine in lieu of bromine in the procedure of the first example of this paragraph, the corresponding 7,10-dichloro-7,IO-dihydro compounds and the 7-chloro and 10-chloro compounds are respectively prepared.

EXAMPLE 17 The 2-acetoxy-7-bromo l ,6-methano-[ l0]annulene is treated in accordane with the procedure as set forth in Example 10, paragraphs 4 to 10, to prepare, for example, 2-(2-hydroxy-3-isopropylaminoprop-l-yloxy)- 7-bromo-1,6-methano-[ l0]annulene.

In a similar manner, 2-(2-hydroxy-3-isopropylaminoprop-1-yloxy)-10-bromo-1,6-methano-[ l0]annulene is prepared. In like manner, the like procedure will prepare the similar compounds in the difluoromethano series.

EXAMPLE 18 The thus prepared compound (200 mg.) is refluxed in 5 ml. of acetone for 10 hours. The solvent is then removed under vacuum to provide the 2-(2,2-dimethyl-3- isopropyl-S-oxazolidinylmethoxy)-7-bromo-1,6- methano-[ l0]annulene product.

The thus prepared compound (200mg) is dissolved in 500 ml. of ether and 1.1 equivalents of n-butyllithium is added thereto. The mixture is stirred for 30 minutes at room temperature. After this time, tributylborate (0.5 ml.) is then added and the mixture is stirred for one hour. Alkaline hydrogen peroxide (1.1 equivalents) is then added to the solution and, after 30 minutes, 5 ml. of dilute hydrochloric acid is added and the mixture is stirred for one hour. Excess aqueous sodium bicarbonate is added to the solution and it is then extracted with ether, washed with water, dried and evaporated to give 2-( 2-hydroxy-3-isopropylaminoprop-lyloxy)-7-hydroxy-l ,6-methano-[ l0]annulene.

The hydroxy annulene thus prepared (200 mg.) is dissolved in 3 ml. of diglyme and to the resultant mixture is added one equivalent of sodium hydride. The resultant mixture is then stirred for 30 minutes and after this time one equivalent of methyl iodide is added.

After three hours, water and ether are added and the ethereal layer is separated, dried and evaporated to give 2-(Z-hydroxy-B-isopropylaminoprop-l-y|oxy)-7- methoxyl ,6-mcthano-l l0]annulene. 5 By substitution of alternate alkyl bromides and allyl bromide for methyl iodide in the above procedure, the corresponding 7-alkyloxy and allyloxy compounds are prepared.

The 7-hydroxy group can also be esterified as set forth in Example 10, paragraphs 1 and 3, to prepare the corresponding 7-carboxylic acyloxy compounds.

The foregoing methods by which the 7-bromo or chloro group can be converted to the 7-hydroxy, acyloxy, alkyloxy, or allyloxy groups in order to prepare the corresponding 7-substituted compounds in the 2-(2-hydroxy-3-monosubstituted (di substituted according to Example 19) aminoprop-l-yloxy) series including the 1,6-methano and 1,6-difluoromethano compounds; are also completely and identically applicable to the IO-bromoor chloro starting compounds prepared as described in this example. Thus, these preparations are useful for the preparation of the corresponding 10-hydroxy, carboxylic, acyloxy, alkyloxy, or allyloxy compounds in the 2-(2-hydroxy-3-monosubstituted or di-substituted aminoprop-l-yloxy)-series including the 1,6-methano and 1,6-difluoromethano compounds.

The following examples further illustrate the alternate method for preparing a 2-(2-hydroxy-3-disub- 30 stituted amino-prop-l-yloxy) compound of the present invention.

EXAMPLE 19 2-(2-Hydroxy-3-isopropylaminoprop-1-yloxy)-7- bromo-l,6-methano-[10]annulene (200 ml.) is dissolved in 5 ml. of ethanol containing 250 mg. of sodium carbonate and 1 equivalent of n-butylbromide. The mixture is heated to 100C. in an autoclave for 6 hours. After this time, it is cooled and poured into water. The aqueous solution is extracted with chloroform and the extracts are dried and evaporated to give 2-(2-hydroxy- 3-isopropyl-n-butylaminoprop-1-yloxy)-7-bromo-l ,6- methano-[ l0]annulene.

The foregoing can also be practiced using alternate alkyl or alkenyl bromides to prepare the corresponding disubstituted amino compounds.

The following examples further illustrate the method by which the oxazolidine derivatives of the compounds of the present invention are prepared.

EXAMPLE 20 2-(2-Hydroxy-3-isopropylaminoprop-1-yloxy)-1,6-

methano-[10]annulene (200 mg.) is dispersed into 1 ml. of acetone and 50 ml. of a trace (ca. 25 mg.) of p-toluenesulfonic acid and the resultant mixture is refluxed for 2 hours. After this time, 0.5 ml. of triethylamine is added and the resultant mixture poured into water. The organic layer is separated, washed with water, dried and evaporated to give 2-(2,2-dimethyl-3- isopropyl-S-oxazolidinylmethoxy)-1,6-methano- [l0]annulene.

The resultant mixture is then evaporated to dryness to give 2 3-isopropyl-5-oxazolidenylmethoxy)-l ,6- difluoromethano-[ l]annulene.

In like manner, the foregoing procedures can be used to prepare the other oxazolidine derivatives hereof, for example,

2-(2,2-( l ,S-pentylene )-3-isopropyl-5- oxazolidinylmethoxy)- l ,6-methano-[ l0]annulene.

The following example illustrate the method by which the pharmaceutically acceptable non-toxic salts of the compounds hereof are prepared.

EXAMPLE 22 One gram of 2-(2-hydroxy-3-aminoprop-l-yloxy)- 1,6-methano-[l01annulene is added to I00 ml. of diethyl ether at 0C. and this solution treated with hydrogen chloride. The mixture is allowed to stand for one hour and then warm to room temperature. The mixture is then evaporated to give 2-(2-hydroxy-3-aminopropl-yloxy)-l ,6-methano[ l0lannulene hydrochloride.

What is claimed is:

l. A compound selected from the group of compounds represented by the following formulas:

wherein,

X is hydrogen or fluoro; each of R, R" and R" independently is hydrogen, alkyl of one to eight carbon atoms, inclusive, or cycloalkyl of three to six carbon atoms, inclusive; I R is allyl or alkyl of one to three carbon atoms; R is allyl or alkyl of one to three carbon atoms; R is alkyl or alkenyl, each of up to six carbon atoms. 2. A compound selected from those of Formula A of claim 1.

3. A compound selected from those of claim 2 wherein each R is hydrogen.

4. A compound selected from those of Formula B of claim 1.

5. A compound selected from those of claim 4 wherein R is allyl and X is hydrogen.

6. A compound selected from those of claim 5 wherein one R is hydrogen and the other is isopropyl.

7. A compound selected from those of claim 5 wherein one R is hydrogen and the other is t-butyl.

8. A compound selected from those of claim 4 wherein R is allyl and X is fluoro.

9. A compound selected from those of claim 8 wherein one R is hydrogen and the other is isopropyl.

10. A compound selected from those of claim 8 wherein one R is hydrogen and the other is t-butyl.

11. A compound selected from those of Formula D of claim 1.

12. A compound selected from those of claim 11 wherein X is hydrogen, one R is hydrogen and the other is isopropyl.

13. A compound selected from those of claim 11 wherein X is hydrogen, one R is hydrogen and the other is t-butyl.

14. A compound selected from those of claim 11 wherein X is fluoro, one R is hydrogen and the other is isopropyl.

15. A compound selected from those of claim 11 wherein X is fluoro, one R is hydrogen and the other is t-butyl.

16. A compound selected from those of Formula A of claim 1 wherein X is hydrogen, one R is hydrogen and the other is isopropyl.

17. A compound selected from those of Formula A of claim 1 wherein X is fluoro, one R is hydrogen and the other is isopropyl.

18. A compound selected from those of Formula A of claim 1 wherein X is hydrogen, one of R is hydrogen, and the other is t-butyl.

19. A compound selected from those of Formula A of claim 1 wherein R is fluoro, one R is hydrogen and the other is t-butyl.

20. A pharmaceutically acceptable non-toxic salt of a compound selected from those of claim 1. 

2. A compound selected from those of Formula A of claim
 1. 3. A compound selected from those of claim 2 wherein each R1 is hydrogen.
 4. A compound selected from those of Formula B of claim
 1. 5. A compound selected from those of claim 4 wherein R2 is allyl and X is hydrogen.
 6. A compound selected from those of claim 5 wherein one R1 is hydrogen and the other is isopropyl.
 7. A compound selected from those of claim 5 wherein one R1 is hydrogen and the other is t-butyl.
 8. A compound selected from those of claim 4 wherein R2 is allyl and X is fluoro.
 9. A compound selected from those of claim 8 wherein one R1 is hydrogen and the other is isopropyl.
 10. A compound selected from those of claim 8 wherein one R1 is hydrogen and the other is t-butyl.
 11. A compound selected from those of Formula D of claim
 1. 12. A compound selected from those of claim 11 wherein X is hydrogen, one R1 is hydrogen and the other is isopropyl.
 13. A compound selected from those of claim 11 wherein X is hydrogen, one R1 is hydrogen and the other is t-butyl.
 14. A compound selected from those of claim 11 wherein X is fluoro, one R1 is hydrogen and the other is isopropyl.
 15. A compound selected from those of claim 11 wherein X is fluoro, one R1 is hydrogen and the other is t-butyl.
 16. A compound selected from those of Formula A of claim 1 wherein X is hydrogen, one R1 is hydrogen and the other is isopropyl.
 17. A compound selected from those of Formula A of claim 1 wherein X is fluoro, one R1 is hydrogen and the other is isopropyl.
 18. A compound selected from those of Formula A of claim 1 wherein X is hydrogen, one of R1 is hydrogen, and the other is t-butyl.
 19. A compound selected from those of Formula A of claim 1 wherein R is fluoro, one R1 is hydrogen and the other is t-butyl.
 20. A pharmaceutically acceptable non-toxic salt of a compound selected from those of claim
 1. 